Addition to coumarins

The scheme illustrates that E-olefins lead to virtually pure trans-adducts. However, Z-olefins produce mixtures of as- and tra .9-methylenecyclopentanes, the loss of stereospecificity being partially due to Z/E isomerization of the olefin under the reaction conditions. The stepwise nature of the addition also contributes to the loss in stereochemical integrity. Although in these examples the palladium catalyst used was the prereduced tetrakis(triphenylphosphane)palladi-um(0), studies have shown that there is no significant difference in yield between this approach and the use of palladium acetate with triisopropyl phosphite. Indeed, this latter system is often much easier to apply since the nature of the phosphane can be altered and the handling of air-sensitive complexes is avoided. The procedure with teti akis(triphenylphosphane)palladium(0) as catalyst is exemplified by the addition to coumarin. 

Phytoalexins are low molecular weight compounds produced in plants as a defense mechanism against microorganisms. They do, however, exhibit toxicity to humans and other animals in addition to microbes (30). Coumarins, glycoalkaloids, isocoumarins, isoflavonoids, linear furanocoumarins, stilbenes, and terpenes aU. fall into the category of phytoalexins (31). Because phytoalexins are natural components of plants, and because their concentration may increase as a response to production and management stimuli, it is useful to recogni2e the possible effects of phytoalexins in the human diet. 

The couplings of vicinal protons in 1,2-disubstituted alkenes lie in the range 6-12 Hz for cis protons (dihedral angle 0°) and 12-17 Hz for trans protons (dihedral angle 180°), thus also following the Karplus-Conroy equation. Typical examples are the alkene proton AB systems of coumarin (16a, cis) and tra 5-cinnamic acid (16b), and of the cis-trans isomers 17a and b of ethyl isopente-nyl ether, in addition to those in problems 3, 4, 8, 11, 13 and 38. 

In addition to their work on naphthocoumarins, Sen and Kakaji showed that 4-t-butyl-2-hydroxyphenones 50 gave exclusively coumarins 51 when treated with various anhydrides in the presence of their corresponding sodium carboxylates. They saw similar results with 4-t-amyl-2-hydroxyphenones. 

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

FIG. 4 Time-resolved fluorescence Stokes shift of coumarin 343 in Aerosol OT reverse micelles, (a) normalized time-correlation functions, C i) = v(t) — v(oo)/v(0) — v(oo), and (b) unnormalized time-correlation functions, S i) = v i) — v(oo), showing the magnitude of the overall Stokes shift in addition to the dynamic response, wq = 1.1 ( ), 5 ( ), 7.5 ( ), 15 ( ), and 40 (O) and for bulk aqueous Na solution (A)- Points are data and lines that are multiexponential fits to the data. (Reprinted from Ref 38 with permission from the American Chemical Society.)... 

Coumarin dibromide has been prepared by the addition of bromine to coumarin in chloroform solution. 1-2... 

Simple phenolic compounds include (1) the phenylpropanoids, trans-cinnamic acid, p-coumaric acid and their derivatives (2) the phenylpropanoid lactones called coumarins (Fig. 3.4) and (3) benzoic acid derivatives in which two carbons have been cleaved from the three carbon side chain (Fig. 3.2). More complex molecules are elaborated by additions to these basic carbon skeletons. For example, the addition of quinic acid to caffeic acid produces chlorogenic acid, which accumulates in cut lettuce and contributes to tissue browning (Fig. 3.5). 

Additives can be consumed at the cathode by incorporation into the deposit and/or by electrochemical reaction at the cathode or anode. Consumption of coumarin in the deposition of nickel from a Watts-type solution has been studied extensively. Thus, in this section we discuss the consumption of coumarin, which is used as a leveler and partial brightener. In a series of papers (33, 36), Rogers and Taylor, described the effects of coumarin on the electrodeposition of nickel. They found that the coumarin concentration decreases linearly with time at —960 mV (versus SCE and 485 to 223 rpm at a rotating-disk electrode, for plating times of 8 to 75 min. A rotating-disk electrode was used to achieve a uniform and known rate of transport of additive to the cathode. Rogers and Taylor found that the rate of coumarin consumption is a function of coumarin bulk concentration. Figure 10.16 shows that the rate of consumption... 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

Coumarin is widely distributed in the plant kingdom, but for commercial use has been mostly produced synthetically for many years. In addition to its use in the perfumery, cosmetic and related industries, coumarin has several other industrial applications. Formerly, large quantities of coumarin were used in the food industry, mostly associated with vanillin, for flavouring chocolates, baked goods, and in cream soda-flavoured beverages (Perone, 1972), but since 1954 its use as a direct food additive has been suspended in the United States (Boisde Meuly, 1993 Lake, 1999). 

In addition to the presence of natural coumarin derivatives, phytochemical analysis found that dong quai also contains ferulic acid and osthole as ingredients. Ferulic acid was reported to have antithrombotic activity (38). Similarly, study using the closely related Angelica pubescens also found osthole to be antithrombotic (39). These two chemical constituents exert their antithrombotic effects by interfering with different pathways responsible... 

Aliphatic primary and secondary amines attack the 1,2-bond of coumarins to give various derivatives depending on the reaction conditions and substituents on the substrate. In addition to the expected amides (280) from coumarin itself, some /3-amino amides (281) are obtained from 4-hydroxycoumarin. In addition, the latter reacts with secondary aliphatic and primary aromatic amines to yield substitution products such as 4-piperidinocoumarin... 

In addition to the examples of coumarin syntheses given in the reviews mentioned above and in the treatise on heterocyclic compounds (B-51MI22400), more recent studies have made use of the Perkin synthesis. These include the use of substituted phenoxyacetic acids to prepare 3-phenoxycoumarins (78CI(L)628> and the synthesis of chlorocoumarins from chlorosalicylaldehydes (81T2613). The use of DBU in place of sodium acetate was necessary to effect the ring closure of a number of o-hydroxyketones (78BCJ1907). 

The coumarin is probably derived from the initial acylated hydroxyacetophenone which, in addition to undergoing a Baker-Venkataraman rearrangement, may cyclize through an intramolecular aldol condensation. Elimination of water then gives rise to the coumarin (Scheme 161). 

Isocoumarins have received less attention than coumarins and yet they form a group of naturally occurring lactones which possess a range of biological activity. In addition to a review of the chemistry of isocoumarins (64CRV229), an earlier paper evaluated potential routes to their synthesis (48JOC477) and a more recent survey is given in Rodd s treatise... 

Coumarins show quite diverse biological activity and, in addition to their anticoagulant properties, have value as vasodilators (Chromonar 718 and Visnadin 719), anthelmintics (Haloxon 720) and diuretics (mercumallylic acid 721), whilst Hymecromone (722) is a... 

This compound is also of the coumarin family. The fonnula is 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin. In addition to use in anticoagulant therapy in medicine, the compound also has been used as a major ingredient in rodenhcides, where the objective is to induce bleeding and, when used in heavy doses, is thus lethal. The compound can be prepared by the condensation of benzylidene-acetone and 4-hydroxycoumann. 

Unlike coumarin, chromone (206) undergoes efficient unsensitized photoaddition to tetramethylethylene, cyclopentene, ketene dimethyl acetal, and but-2-yne.180 The major product of such an addition to tetramethylene is the cis-fused cyclobutane derivative (207) the formation of the two minor products (208 and 209) is easily rationalized. Added benzophenone has no visible effect on this cycloaddition, which is therefore believed to involve the attack of triplet chromone on the ground-state alkene. Photoaddition to furo-chromones has also been studied,179 and the photosensitized cyclo-... 

The study of this cycloaddition and its mechanism is complicated by the formation in small yield of additional photoproducts. Irradiation of phenanthraquinone (308) in, for example, 2-methylpropene affords the oxetane (309), arising by 1,2-cycloaddition of the alkene to the carbonyl, in addition to the expected 1,4-dioxene (310).334 Oxetanes are the principal products of photoaddition of phenanthraquinone to benzofuran, furano[3,2-y]coumarin, and isocoumarin.329 A further product has the structure (311), and is undoubtedly the... 

As in five-membered heterocycles, the introduction of a carbonyl group produces a dramatic effect on the photoreactivity. Pyran-2-ones undergo other electrocyclic processes in addition to those discussed in preceding sections.213 Photorearrangement, however, does not occur in the coumarin nucleus, although a photo-Fries rearrangement of 3-benzoyloxy-6,7-... 

Addition to six-membered oxygen heterocycles is also common. The photocycloaddition of 5,7-dimethoxycoumarin to tetramethylethylene has been described,269 and 4-hydroxycoumarin (326) undergoes facile addition to cyclohexene on direct irradiation to give the cyclobutane (327)270 analogous additions to a variety of other alkenes have been reported, and the cycloaddition of 4-methoxycoumarin to 2-methylpropene has been employed in a synthesis of l,2-dihydrocyclobuta[c]coumarin.271 Photoaddition of the 1,2-bisenol lactone (328) to tran.s-stilbene yields propellane (329),272 and [ 2 + 2] cycloaddition is observed along with other competing photoreactions on irradiation of chromone in the presence of alkenes.273... 

The necessary amino aldehydes are accessible from widely available amino acids and amino alcohols. In addition to N,N-dimethyl barbituric acid shown in Figure 5.3, other 1,3-dicarbonyl compounds can be employed, such as cydohexane-1,3-diones or coumarines (Figure 5.5). 

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